Signal transducers and activators of transcription (Stat) proteins are a recently identified class of transcription factors responsible for mediating may cytokine-induced responses. These proteins exist in a latent form in the cytoplasm and become phosphorylated by the Janus kinase (JAK) family of tyrosine kinases following cytokine-receptor interactions. Once phosphorylated, Stat proteins dimerize, translocate to the nucleus, and bind to specific DNA sequences to regulate gene transcription (Ihle, 1995; Schindler and Darnell, 1995). Of the presently know Stat proteins, only Stat6 is activated in response to the cytokine interleukin-4 (IL-4) (Kotanides and Reich, 1993; Hou et al, 1994; Schindler et al, 1994; Quelle et al., 1995). IL-4 is secreted by several cell types including stimulated T lymphocytes, mast cells, and basophils (Howard et al., 1982; Lee et al, 1986; Paul and Ohara, 1987; Yoshimoto and Paul, 1994; Sad et al., 1995). While initially identified by its ability to support the growth and differentiation of B lymphocytes costimulated with submitogenic doses of anti-immunoglobulin (Howard et al., 1982), IL-4 is now known to have pleiotropic effects on the immune system. IL-4 is essential for the induction of immunoglobulin E (IgE) synthesis by activated B lymphocytes and influences class switching to IgG1 as well (Vitetta et al, 1985; Coffman et al., 1986). B cells stimulated with IL-4 increase their cell surface expression of major histocompatibility complex (MHC) class II molecules (Noelle et al., 1984), IL-4 receptor (IL-4R) (Ohara and Paul, 1988), and the low affinity IgE receptor CD23 (Conrad et al., 1987). IL-4 also induces the proliferation of T lymphocytes and is important for the differentiation of T helper 2 (Th2) cells (Le Gros et al., 1990; Swain et al., 1990). Indeed, the analysis of IL-4-deficient mice generated by gene targeting in embryonic stem (ES) cells has confirmed the importance of this cytokine in mediating many of these responses (Kuhn et al., 1991; Kopf et al., 1993).
IL-4-induced responses result from the interaction of ligand with a cell surface receptor composed of a cytokine-specific a chain and the common gc chain also used by IL-2 (Takeshita et al., 1992). IL-7 (Nognchi et al, 1993; Kondo et al, 1994), IL-9 (Russell et al., 1994) and IL-15 (Giri et al., 1994) receptors. Recent studies have shown that the a chain of the IL-4R is also a component of the high affinity IL-13 receptor (Lin et al., 1995; Zurawski et al, 1995; Hilton et al., 1996). Engagement of the IL-4R leads to the activation of at least two distinct signaling pathways. One involves the activation of Stat6 through phosphorylation by Jak1 and Jak 3 (Johnston et al., 1994; Witthuhn et al., 1994). The Stat pathway is thought to be important because the promoters of several genes know to be regulated by IL-4 contain the consensus Stat6-binding site TTCN4GAA (Schindler et al., 1995), and fragments of promoters of Ie and other genes containing this sequence bind Stat6 present in extracts from cells stimulated with IL-4 (Ichiki et al., 1993; Kotanides and Reich, 1993; Schindler et al., 1994). In addition to Stat6 activation, stimulation of the IL-4R has also been shown to induce the phosphorylation of an insulin receptor substrate (IRS) termed 4PS or IRS-2 (Keegan et al., 1994; Sun et al., 1995). Activated IRS-2 associates with phosphatidylinositol 3-kinase and may be responsible for certain IL-4-induced responses. For example, cell lines transfected with an IL-4R mutant that in incapable of inducing the tyrosine phosphorylation of IRS-2 have an impaired ability to proliferate in response to IL-4 (Keegan et al., 1994).